International Journal of Environmental Research and Public Health

Article IQOSTM vs. e-Cigarette vs. Tobacco Cigarette: A Direct Comparison of Short-Term Effects after Overnight-Abstinence

Karolien Adriaens 1,* , Dinska Van Gucht 1,2 and Frank Baeyens 1

1 Faculty of Psychology and Educational Sciences, KU Leuven—University Leuven, Tiensestraat 102, 3000 Leuven, Belgium; [email protected] (D.V.G.); [email protected] (F.B.) 2 Applied Psychology Unit, Thomas More University of Applied Sciences, Molenstraat 8, 2018 Antwerp, Belgium * Correspondence: [email protected]; Tel.: +32-16-329-088



Received: 13 November 2018; Accepted: 14 December 2018; Published: 18 December 2018


Abstract: Introduction: Research from Philip Morris International’s science division on its Heat-not-Burn product IQOSTM focused on its chemical, toxicological, clinical, and behavioral aspects. Independent research on the experiences and behavioral aspects of using IQOSTM, and how it compares to e-cigarettes, is largely lacking. The current randomized, cross-over behavioral trial tried to bridge the latter gaps. Methods: Participants (n = 30) came to the lab on three consecutive days after being overnight smoking abstinent. During each session, participants used one of three products (cigarette, e-cigarette, or IQOSTM) for five minutes. Exhaled CO (eCO) measurements and questionnaires were repeatedly administered throughout the session. Results: Smoking a cigarette for five minutes resulted in a significant increase of eCO, whereas using an IQOSTM resulted in a small but reliable increase (0.3 ppm). Vaping did not affect eCO. Cigarette craving reduced significantly after product use, with the decline being stronger for smoking than for e-cigarettes or IQOSTM. Withdrawal symptoms declined immediately after smoking or using IQOSTM, and with some delay after vaping. IQOSTM scored higher in terms of subjective reward/satisfaction and was slightly preferred to the e-cigarette. Discussion: Short-term use of IQOSTM has a minimal impact on eCO, is equally effective in reducing cigarette craving and withdrawal symptoms as an e-cigarette, and is slightly preferred.

Keywords: tobacco harm reduction; electronic cigarettes; heat-not-burn tobacco products

1. Introduction People who choose to smoke, subject themselves to one of the leading causes of years of potential life lost (YPLL) [1–3]. Many smokers try to quit, but traditional smoking cessation aids, or solely relying on willpower, unfortunately, only help a small minority to quit successfully and, especially, to remain smoking abstinent [4–7]. More specifically, after one particular quit-attempt only 3–5% of smokers solely relying on willpower achieve long-term (six to 12 months) smoking abstinence [7], whereas these rates double or at best triple when using Nicotine Replacement Therapy (NRT) or smoking cessation medication [5,6]. For example, in a recent analysis of the long-term outcomes of the Stop Smoking Services in England (standardly providing a combination of behavioral counseling plus NRT or smoking cessation medication), quit rates after one year were only around 8% [4]. Tobacco Harm Reduction (THR)—encouraging the substitution of low-risk alternatives—may be an alternative, more feasible way of attaining smoking cessation, especially for those smokers who cannot or do not want to cease all tobacco and/or nicotine consumption [8–11]. Alternative low-risk

Int. J. Environ. Res. Public Health 2018, 15, 2902; doi:10.3390/ijerph15122902 www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2018, 15, 2902 2 of 20 nicotine products include smokeless-tobacco (e.g., Swedish snus), long-term use of NRT, and electronic cigarettes (e-cigarettes) [2,11,12]. Almost a decade of extensive research on e-cigarettes has recently been evaluated and summarized in several comprehensive reviews [13–15]. These reviews, as well as individual studies, unanimously concluded that, beyond any doubt, using an e-cigarette (“vaping”) presents substantially less health risks than smoking; and suggested that “e-cigarette health risks are unlikely to exceed 5% of those associated with smoked tobacco products, and may well be substantially lower” [13–18]. In addition, there is convincing evidence that for many smokers, e-cigarettes are a valuable tool to assist in quitting smoking [13–15,19–21]. As reported in the majority of the well-conducted prospective observational cohort studies, the odds ratios of (self-reported) quitting (OR 2.69–7.88; 20–42% quitters) are substantially higher in smokers who self-select to use e-cigarettes in a quit-attempt compared to those who do not [22–25]. An important contributor to quit-smoking success seems to be regular (daily) and/or long-term use of efficient e-cigarettes. In the same vein, according to national (UK/France) and EU cross-sectional population data, about half (41–52%) of the current daily e-cigarette users report to have quit smoking, completely [26–29]. However, the prevalence of current e-cigarette use in the EU population (15 years and older) centers around no more than about 2% (4% in current smokers, 4% in ex-smokers, 0% in never smokers) [30]. Among the US population, prevalence of current adult e-cigarette use is estimated at about 3% [31]. Additionally, among current e-cigarette users, a considerable percentage (about 50%) use both cigarettes and e-cigarettes (“dual use”), and many of those dual users do not seem able, nor willing to completely quit smoking by switching to vaping [26,32]. From a health perspective, reducing smoking is a step in the good direction, but smoking no more than a few cigarettes per day still has significant effects on premature mortality and overall morbidity [33,34]. A partial explanation of dual use, and of the relatively low uptake of vaping by smokers, more generally, could be that vaping is not a satisfactory alternative for some smokers who want to switch to a low-risk alternative [35,36]. For example, a recent study with confirmed smokers found that 59% of the participants had tried out vaping but indicated several aspects they did not like about vaping, such as the (sensory and behavioral aspects of the) vaping experience, the material of which the e-cigarette is composed, the “chemical composition” of the e-liquids and the technical complexity of vaping [35]. This indicates that not all smokers may benefit from trying out vaping. As the THR vision implies offering (that is, developing, correctly informing about, and encouraging the use of) any tool that reduces the harms caused by smoking, it is our position that the availability of several different alternatives for smoking should be welcomed, rather than seen as a threat. This allows smokers to freely choose, try out, and find products that are sufficiently attractive and suit them best to reduce the harmful effects from smoking [9]. One other alternative could be the new Modified-Risk Tobacco Products (MRTPs), or more specifically, the Heat-not-Burn tobacco products (HnB products) developed by several tobacco companies [37,38]. Different HnB products exists, but one of the most prominent is the IQOSTM, developed by Philip Morris International (PMI) [38]. The IQOSTM contains a holder which heats a tobacco stick (HEETS or heatsticks) below 350 ◦C, such that an aerosol is produced which the user can inhale; using an IQOSTM closely mimics the smoking experience [38]. Based on their own research, PMI concluded (i) that no combustion occurs when the IQOSTM is used, (ii) that the aerosol from the IQOSTM contains substantially less (around 90%) Harmful and Potentially Harmful Constituents (HPHCs), compared to cigarettes, (iii) that this reduction in the HPHCs levels in the aerosol leads to reduced exposure and to reduced (in vitro and in vivo) toxicological effects, (iv) and that the risk of smoking-related diseases is probably reduced [38–43]. A substantial part of the research conducted by PMI included the clinical assessment of the IQOSTM in humans [38]. First, three open-label, randomized, cross-over studies investigated nicotine pharmacokinetics and concluded that in smokers using the IQOSTM, a similar pharmacokinetic profile is obtained compared to smoking (IQOSTM: Cigarette ratios for maximal concentration, Int. J. Environ. Res. Public Health 2018, 15, 2902 3 of 20

Cmax; and overall nicotine exposure (area under the concentration-time curve), AUC0–last and TM AUC0–∞, varied between 88–104%) [44,45]. In line with this, the IQOS appeared to be equally effective in controlling cigarette craving (urge-to-smoke measurements) as smoking cigarettes [44,45]. Second, several PMI studies investigated biomarkers of exposure to the HPHCs, as well as self-reported subjective measures (e.g., urge-to-smoke, product evaluation) in smokers switching to the IQOSTM, continuing smoking or quitting smoking, using randomized and controlled confinement studies in Europe and Japan [46–49]. In general, these studies included a four-week screening period, a confinement period of five days in which randomization took place, a safety follow-up period, and sometimes an ambulatory period (follow-up period of 90 days). These studies concluded that, compared to continuing smoking and already after five days, switching to the IQOSTM resulted in significant reductions (34–94%) in the biomarkers of exposure to several HPHCs [46,47]. This effect was maintained upon follow-up and was comparable with reductions in biomarkers of exposure, due to complete smoking abstinence [46–49]. In addition, participants switching to the IQOSTM reported similar and stable levels in the urge to smoke compared to continuing smoking. Product evaluations of the IQOSTM and cigarettes differed across studies, but a longitudinal study showed that from day 1 to 30, the cigarette was rated better, whereas from day 30 onwards, the IQOSTM achieved similar scores [49]. A recent systematic literature review confirmed that most of the research involving HnB products, so far, has been conducted by tobacco companies, such as PMI and British American Tobacco (BAT), themselves (20 out of the 31 included studies), and highlighted that the few independent research conducted, mainly focused on the chemical aspects of the HnB aerosol [50]. A comparison of results is complicated by the heterogeneity of the HnB products studied and by the different measurement methods used [50]. Nevertheless, the overall picture that emerges from independent aerosol studies largely confirmed PMI’s findings, with respect to the levels of nicotine, carbon monoxide (CO), total particulate matter (TPM), and the main other HPHCs in the IQOSTM aerosol (e.g., volatile organic compounds, VOCs; aldehydes; polycyclic aromatic hydrocarbons; and tobacco-specific nitrosamines, TSNAs) [50–58]. Independent research with respect to (in vitro and in vivo) IQOSTM toxicology is rare (an exception being a study by Leigh and colleagues), whereas, human clinical and behavioral/experiential studies focusing on the IQOSTM use is virtually nonexistent [50,59]. Caponnetto and colleagues were the first to independently investigate the effects of using IQOSTM on exhaled CO (eCO) levels, using a randomized cross-over trial in smokers [60]. A comparison was made between the two different HnB products (IQOSTM or GLOTM, with the latter being a HnB product similar to IQOSTM but developed by BAT) and the cigarette brand regularly smoked by participants [37,60]. First, participants were trained on how to use the HnB products at screening. Next, participants were instructed to abstain from smoking for 12 h before each of the three study days, on which they could use one of the three products following a specific puffing regime [60]. Measurements were obtained at specific times throughout the sessions. The authors concluded that, unlike what is observed when smoking a cigarette, using the HnB products did not result in increased eCO levels [60]. Two limitations of this study were that no data concerning craving and subjective experiences were obtained, and that no comparisons with vaping were made. Therefore, we conducted a three-day randomized cross-over trial, focusing on the behavioral and experiential effects of the short-term use of the HnB product IQOSTM, versus an e-cigarette, versus a regular cigarette, in current smokers who were novice users for both IQOSTM and e-cigarettes. The two main research aims of the study reported here were: (1) to investigate the effect of using an IQOSTM on eCO, acute cigarette craving, withdrawal symptoms, and subjective positive and negative experiences after overnight smoking abstinence, compared to using an e-cigarette or a regular tobacco cigarette; and (2) to investigate which product (e-cigarette or IQOSTM) would be preferred. Int. J. Environ. Res. Public Health 2018, 15, 2902 4 of 20

2. Materials and Methods

2.1. Participants We recruited Dutch and English speaking participants via various channels around the University of Leuven (i.e., distribution of flyers in University buildings and local newspaper shops, social media). Inclusion criteria, based on (own) previous research [60,61], were, being a smoker for at least three years, smoking at least 10 cigarettes per day (CPD), having no intention to quit smoking in the following three months, and willing/accepting to try out several less harmful alternatives. Exclusion criteria were currently using any kind of smoking cessation therapy (e.g., smoking cessation medication, NRT, counseling), ever having owned and used an e-cigarette and/or an HnB product, having tried out an e-cigarette and/or an HnB product, during the past month, being pregnant or breast feeding, and having one or more severe medical conditions (i.e., a psychiatric condition, respiratory or heart disease, drug use other than nicotine, diabetes). A total of 46 interested individuals signed up for the intake session, of whom 34 completed all sessions. After data collection, another four participants were excluded due to not complying with the critical inclusion criteria (i.e., e-cigarette use in recent past, number of CPD substantially <10, eCO level >10 at start of laboratory session). Two participants were not excluded despite minor violations of inclusion criteria (CPD = 9; conflicting answers on two questions assessing intention to quit smoking in the next three months). The main results did not differ when excluding or including these two participants who slightly deviated from the (secondary) inclusion criteria, but including them allowed to maintain the perfectly balanced design. The final sample size, thus, consisted of 30 participants.

2.2. Materials Three products were used during the laboratory sessions—a regular tobacco cigarette, an e-cigarette and the IQOSTM HnB tobacco product. Participants were asked to bring their habitual tobacco cigarettes, so that they could use one in the corresponding session (see Section 2.3. Study Design and Procedure). During the session in which participants were asked to use the e-cigarette or IQOSTM, we provided each participant with the same product. We used an Eleaf iStick Power 5000 mAh battery, fixed at 8 W, with an Aspire Nautilus 2 tank containing a 1.6 Ohm coil. The e-liquid (“Base Aurora”) contained 18 mg/mL nicotine, a PG/VG ratio of 70/30, to which either a tobacco flavor (“7 Leaves”, 3 vol%) or a menthol flavor (“Mild Winter-Peppermint”, 3 vol%) was added. Both base liquid and flavors were purchased online (https://www.clubderdampfer.de and https://flavourart.com, respectively). Clearomizer type and wattage settings, as well as nicotine concentrations, were based on the results of a study by Farsalinos and colleagues, in which they found that these settings can—conditional on longer puff duration—deliver similar nicotine levels to the aerosol (0.82 mg/12 puffs at 2 s vs. 1.84 mg/12 puffs at 4 s) as combustible tobacco cigarettes (1.99 mg/12 puffs at 2 s) and slightly more than the IQOSTM HnB product (1.40 mg/12 puffs at 2 s vs. 1.41 mg/12 puffs at 4 s) [53]. The IQOSTM was purchased in an official IQOS-shop in the Netherlands, since HnB products are not available in the Belgian market. Both regular and menthol-flavored heat-sticks were purchased. The menthol e-liquid and heat-sticks were only destined for regular menthol cigarette smokers; however, because nobody happened to smoke menthol cigarettes, the menthol products were not used in this study.

2.3. Study Design and Procedure The research protocol was approved by the Societal and Social Ethics Committee of the University of Leuven before the start of the study (G-2017 08 900) and the protocol was preregistered on aspredcited.org (#6896). Prior to the study, interested individuals could contact the first author for more information about the study. Those willing to participate decided, through self-selection, if they were eligible Int. J. Environ. Res. Public Health 2018, 15, 2902 5 of 20 to participate and subsequently subscribed for the intake session via the Experiment Management System (EMS) of the Faculty of Psychology and Educational Sciences [62]. Depending on the enrolments, intake sessions were carried out in group (with a maximum of six participants) or individually, and lasted approximately 30 min. All participants were provided with a brief explanation about the safety and practical use of the products, and the course of the study. Int. J. Environ. Res. Public Health 2018, 15, x FOR PEER REVIEW 5 of 20 Next, participants signed the informed consent form, filled out the intake questionnaire, and performed anperformed eCO-measurement. an eCO-measurement. At the end ofAt thethe session, end of wethe scheduledsession, we the scheduled three laboratory the three sessions laboratory with eachsessions participant. with each participant. WeWe usedused aa cross-over,cross-over, counterbalanced,counterbalanced, within-subjectswithin-subjects design for the laboratory sessions. ParticipantsParticipants came to to the the lab lab (individually (individually or orin ingroup, group, with with a maximum a maximum of three of three participants) participants) on three on threeconsecutive consecutive days, each days, time each at time the same at the hour same of hour the day; of the each day; session each lasted session 70 lasted to 80 min 70 to and 80 followed min and followedthe same the procedure same procedure (see Figure (see Figure 1 for1 allfor allproced procedureure details). details). Before Before each each laboratory session,session, participantsparticipants neededneeded to to abstain abstain from from smoking smoking for for 12 h.12 Ath. theAt startthe start of the ofsession the session (T0), participants(T0), participants filled outfilled questionnaires out questionnaires and performed and performed an eCO-measurement. an eCO-measurement. In the corresponding In the corresponding session, participants session, TM receivedparticipants a brief received rehearsal a brief on how rehearsal to use theon how e-cigarette to use or the IQOS e-cigarette. Next, or participants IQOSTM. Next, could participants use one of thecould three use products one of the ad three lib for products five minutes ad lib outsidefor five minutes the building outside (only the one building cigarette (only or heat-stickone cigarette were or allowed).heat-stick Inwere each allowed). session, In only each one session, product only was one used product and thewas order used ofand product the order use of over product the days use wasover completelythe days was counterbalanced completely co betweenunterbalanced participants between to controlparticipants for order to control effects. for Finally, order ateffects. fixed momentsFinally, at (T1,fixed T2, moments T3, T4, and (T1, T5; T2, see T3, Figure T4, and1) T5; participants see Figure filled 1) participants out questionnaires filled out and questionnaires performed eCOand performed measurements. eCO measurements. Participants who Participants completed wh allo completed sessions received all sessions a compensation received a compensation of 50 € or, if applicable,of 50 € or, if five applicable, credits for five a mandatorycredits for a research mandatory course research within course the psychology within the training. psychology training.

Figure 1.1. Study design and procedure.

2.4.2.4. Outcome Measures 2.4.1. Physiological Measures 2.4.1. Physiological Measures eCO measurements were collected during the intake session and laboratory sessions (T0 to eCO measurements were collected during the intake session and laboratory sessions (T0 to T5), T5), using a piCO+ Smokerlyzer® [63]. The concentration in parts per million (ppm) was noted by using a piCO+ Smokerlyzer® [63]. The concentration in parts per million (ppm) was noted by the the researcher. researcher.

2.4.2. Subjective Effect Questionnaires Questionnaires and instructions on how to fill them out were displayed on the computer screen using Affect 5 [64]. Participants answered by clicking or entering text on the computer keyboard. The intake questionnaire assessed socio-demographics (age, gender, highest educational degree, occupation, marital status, net income per month in €, nationality—all predefined categories except for age and nationality), smoking history (‘age started smoking’, ‘age started regular smoking’, ‘how long smoking’—all open ended), current smoking behavior (‘situations when smoking’, ‘reasons why smoking’—predefined categories; ‘current average smoked CPD’, ‘most important cigarette of the

Int. J. Environ. Res. Public Health 2018, 15, 2902 6 of 20

2.4.2. Subjective Effect Questionnaires Questionnaires and instructions on how to fill them out were displayed on the computer screen using Affect 5 [64]. Participants answered by clicking or entering text on the computer keyboard. The intake questionnaire assessed socio-demographics (age, gender, highest educational degree, occupation, marital status, net income per month in €, nationality—all predefined categories except for age and nationality), smoking history (‘age started smoking’, ‘age started regular smoking’, ‘how long smoking’—all open ended), current smoking behavior (‘situations when smoking’, ‘reasons why smoking’—predefined categories; ‘current average smoked CPD’, ‘most important cigarette of the day’, ‘brand/type of smoked cigarettes’—open ended), motivation to quit smoking (predefined categories), quit-smoking attempts in the past (‘number of attempts’, ‘longest quit-smoking period’—open ended; ‘quit-smoking aids used’, including those used during the longest quit-smoking period—predefined categories), experienced negative health effects of smoking (e.g., “As a smoker I suffer from headaches”; on Likert scales from 1 “Never” to 5 “Always”), mental health status (i.e., suffering from any psychological/psychiatric condition; predefined categories), and tobacco cigarette dependence, using the Fagerström Test for Cigarette Dependence (FTCD) [65]; see AppendixA, Table A1. The questionnaires used during the laboratory sessions included (see Figure1): A visual analogue scale (VAS) assessing cigarette craving, the brief Questionnaire on Smoking Urges (QSU-Brief), the Revised Minnesota Nicotine Withdrawal Scale (MNWS-R), and the modified Cigarette Evaluation Questionnaire (mCEQ, also adapted for e-cigarette and IQOSTM)[66–69]. The VASs were 100 mm, with on the left “No craving at all” and on the right “Very strong craving”, and were administered at each moment (T0 to T5). The QSU-Brief measures the multidimensional aspects of craving, using 10 items rated on a 7-point scale, going from “Strongly disagree” to “Strongly agree”, and was administered at T0, T1, and T5 [66]. The scale allows for the calculation of a general average score, as well as two specific factors (i.e., “The desire and intention to smoke with an anticipation of pleasure from smoking” and “The relief from nicotine withdrawal or negative affect with an urgent and overwhelming desire to smoke”). The MNWS-R measures nicotine withdrawal symptoms using fifteen items rated on a 5-point scale, going from “None” to “Severe”, and was assessed at T0, T1, and T5 [67,68]. The mCEQ assesses the reinforcing effects of smoking and contains three multi-item-domains (“Smoking satisfaction”, “Psychological reward”, “Aversion”) and two single-item-domains (“Enjoyment of respiratory tract sensations”, “Craving reduction”) [69]. All twelve items were scored on a 7-point scale going from “Not at all” to “Extremely”. We adjusted the questionnaire so it was also applicable for the e-cigarette and IQOSTM and assessed the questionnaire solely at T1. Finally, participants were provided with some additional questions (VASs and open-ended questions) on the last day, regarding their preference for the e-cigarette or IQOSTM. For each theme (“Willing to use the product for another five minutes”, “Willing to keep trying or start using the product”, “Desire/intention to go and buy the product”, “Willing to consider using the product to (try to) quit smoking”) we used three VASs, one for the e-cigarette and one for the IQOSTM, with, for each on the left, “Not at all” and on the right “Very much so”, and one VAS that assessed the participants’ preferred choice with on the left “E-cigarette” and on the right “IQOS”. The left and right label of the latter VAS were counterbalanced across participants, and the same was true for the presentation sequence of the first two VASs. Finally, four open-ended questions assessed the weaknesses and strengths of the e-cigarette and IQOSTM, each compared to cigarettes; with, again, a counterbalancing across participants.

2.5. Statistical Analyses We used descriptive statistics (frequencies, means, and standard deviations) to analyze the main variables assessed at Intake and the open questions (weaknesses and strengths of the products), on the last day. Before analyzing the results from the laboratory sessions, we checked the normality assumption. Normality was violated for some individual variables but due to the fact that group sizes were equal (within-subjects design), we decided to still conduct ANOVAs (because of the robustness of the statistic against violations of normality with equal sample sizes) [70]. For most variables of the Int. J. Environ. Res. Public Health 2018, 15, 2902 7 of 20 laboratory sessions we carried out 3 (Condition: cigarette vs. e-cigarette vs. IQOSTM) × 6 (Moment: T0 to T5) ANOVAs, with subsequent planned comparisons. The additional VASs from day 3 were analyzed using t-tests for paired samples. For all analyses conducted, an α-level of 0.05 was used and all analyses were carried out using “Statistica 13.1” (TIBCO Software Inc., Palo Alto, CA, USA) [71].

3. Results

3.1. Participants Participants (n = 30) were on average 22 years old (SD = 3.09) and mostly male (67%). Almost all (93%) were students with at least a high school degree (100%), having a net income of less than 1000 € (73%), and being single (73%). Almost half of the participants were of Belgian nationality (47%) with the remaining being of other nationalities (e.g., Italian, Pakistani, Indian, etc.). Regarding smoking history, participants started smoking on average at the age of 16 (SD = 1.84) and started smoking regularly at the age of 18 (SD = 1.77). One-third had tried (M = 2.00 times, SD = 0.94) to quit smoking in the past, mainly using willpower (90%). The longest quit-smoking period (with all using willpower) had lasted on average five months (SD = 9.02), with a minimum of one month and a maximum of 30 months. Currently, participants smoked, on average, 13 CPD (SD = 3.62), mostly filter cigarettes (79%), they were low-to-moderate cigarette dependent (M FTCD-score = 3.50, SD = 1.96), experienced rare-to-occasional negative health effects of smoking (M = 2.23, SD = 0.48), and had an average eCO level of 7.37 (SD = 3.39). The top three situations when they smoked included drinking alcohol (97%), being with others (93%), and being alone (87%). Reasons why participants smoked were to relax (87%), because they felt like having a cigarette (83%) and for atmosphere and sociability (80%). Only four (13%) participants reported that they currently were trying to reduce smoking. Three of them reported no intention nor concrete plans to quit smoking, and only one expressed concrete plans to quit smoking in the next three months. See AppendixA, Table A1 for all details concerning smoking history and current smoking behavior.

3.2. Physiological Measures Figure2 displays the changes in eCO levels throughout the sessions (see also AppendixA, Table A2). In each laboratory session, participants showed a significant decrease in eCO levels going from 7 ppm at Intake to 3 ppm at the start of each session (T0), p < 0.001, for each condition. No T0 differences in eCO levels were found between conditions, with all ps > 0.20. Smoking a cigarette resulted in increased eCO levels at each moment (T1–T5), compared to T0, all ps < 0.001. From T3 to T4, eCO levels slightly decreased, and continued doing so from T4 to T5, both ps < 0.001. A similar pattern was observed after using the IQOSTM (all ps < 0.05), though in absolute terms, the increase in eCO levels after using the IQOSTM was minimal (0.3 ppm). No changes occurred in the eCO levels after vaping (all ps > 0.06). At each moment (T1–T5), throughout the laboratory session, smoking resulted in significantly higher eCO levels compared to vaping (all ps < 0.001) and using the IQOSTM (all ps < 0.001). Vaping and using the IQOSTM did not lead to reliable differences in eCO levels at any moment (T1–T5; all ps > 0.06). Int. J. Environ. Res. Public Health 2018, 15, 2902 8 of 20 Int. J. Environ. Res. Public Health 2018, 15, x FOR PEER REVIEW 8 of 20

Cigarette E-cigarette IQOS 9

8

7

6

5

4

eCO in ppm eCO in 3

2

1

0 T0 T1 T2 T3 T4 T5

INTAKE LABORATORY SESSION

Figure 2. Exhaled CO (eCO) levels in ppm. Cigarette: MIntake (SE between brackets) = 7.37 (0.62), MT0 = 3.10 (0.33), MT1 = 7.30 (0.49), MT2 = 7.83 (0.52), MT3 = 7.67 (0.49), MT4 = 7.10 (0.48), MT5 = 6.47

Figure(0.41); E-cigarette 2. Exhaled: COMIntake (eCO)= 7.37 levels (0.62), in ppm.MT0 =Cigarette 2.83 (0.33),: MMIntakeT1 =(SE 2.93 between (0.33), M brackets)T2 = 3.07 = (0.37), 7.37 (0.62),MT3 = M 3.17T0 TM =(0.34), 3.10 (0.33),MT4 = M 3.00T1 = (0.33), 7.30 (0.49),MT5 = M 2.83T2 = (0.30);7.83 (0.52),IQOS MT3 :=M 7.67Intake (0.49),= 7.37 M (0.62),T4 = 7.10M (0.48),T0 = 2.73 MT5 (0.35), = 6.47M (0.41);T1 = 3.03 E- cigarette(0.36), M:T2 M=Intake 3.47 = (0.36),7.37 (0.62),MT3 M= 3.57T0 = 2.83 (0.38), (0.33),MT4 M=T1 3.37 = 2.93 (0.34), (0.33),MT5 M=T2 3.07= 3.07 (0.32). (0.37), MT3 = 3.17 (0.34), MT4

= 3.00 (0.33), MT5 = 2.83 (0.30); IQOSTM: MIntake = 7.37 (0.62), MT0 = 2.73 (0.35), MT1 = 3.03 (0.36), MT2 = 3.3. Subjective Effect Questionnaires 3.47 (0.36), MT3 = 3.57 (0.38), MT4 = 3.37 (0.34), MT5 = 3.07 (0.32). 3.3.1. Cigarette Craving 3.3. Subjective Effect Questionnaires The changes in cigarette craving throughout the sessions, are displayed in Figure3 (see also 3.3.1.Appendix CigaretteA, Table Craving A3). After 12 h of smoking abstinence, at the start of each day (T0), participants reported an average cigarette craving of 66 on a scale of 100, with no differences in craving between The changes in cigarette craving throughout the sessions, are displayed in Figure 3 (see also the three conditions (all ps > 0.27). After using each product (T0 to T1), craving for a cigarette reduced Appendix A, Table A3). After 12 h of smoking abstinence, at the start of each day (T0), participants significantly (all ps < 0.001), with the decline being stronger after smoking than after vaping or after reported an average cigarette craving of 66 on a scale of 100, with no differences in craving between using the IQOSTM, both ps < 0.001. The decline observed for the latter two did not differ, F < 1. From T1 the three conditions (all ps > 0.27). After using each product (T0 to T1), craving for a cigarette reduced to T2, only vaping resulted in a significant increase in craving, F(1, 29) = 8.38, p < 0.01. Cigarette significantly (all ps < 0.001), with the decline being stronger after smoking than after vaping or after craving significantly increased at T3, T4, and T5 for all conditions, compared to T1, with all ps < 0.01. using the IQOSTM, both ps < 0.001. The decline observed for the latter two did not differ, F < 1. From At each moment (T1–T5) throughout the laboratory session, smoking resulted in a lower cigarette T1 to T2, only vaping resulted in a significant increase in craving, F(1, 29) = 8.38, p < 0.01. Cigarette craving compared to vaping (all ps < 0.01) and using the IQOSTM (all ps < 0.01). No differences were craving significantly increased at T3, T4, and T5 for all conditions, compared to T1, with all ps < 0.01. observed, at any moment, between using the e-cigarette and the IQOSTM (T1–T5: all ps > 0.43). At each moment (T1–T5) throughout the laboratory session, smoking resulted in a lower cigarette The QSU-Brief, which was presented at T0, T1, and T5, confirmed the results obtained with the craving compared to vaping (all ps < 0.01) and using the IQOSTM (all ps < 0.01). No differences were VASs for cigarette craving (see AppendixA, Table A3). More specifically, at T0 no differences were observed, at any moment, between using the e-cigarette and the IQOSTM (T1–T5: all ps > 0.43). found between conditions (all ps > 0.10). After using each product (T0 to T1), cigarette craving was The QSU-Brief, which was presented at T0, T1, and T5, confirmed the results obtained with the reduced (all ps < 0.001), with the decline being stronger after smoking than after vaping, or after using VASs for cigarette craving (see Appendix A, Table A3). More specifically, at T0 no differences were the IQOSTM, both ps < 0.05. The decline observed, after vaping, and after using the IQOSTM, did not found between conditions (all ps > 0.10). After using each product (T0 to T1), cigarette craving was differ, F < 1. Cigarette craving increased towards the end of each session for each condition (T1 to reduced (all ps < 0.001), with the decline being stronger after smoking than after vaping, or after using T5; all ps < 0.001), with no differences in elevation between conditions (all ps > 0.15). At T1 and T5, the IQOSTM, both ps < 0.05. The decline observed, after vaping, and after using the IQOSTM, did not smoking resulted in lower craving scores compared to vaping (all ps < 0.01) and compared to using differ, F < 1. Cigarette craving increased towards the end of each session for each condition (T1 to T5; the IQOSTM (all ps < 0.01). No differences were observed at any moment between using the e-cigarette all ps < 0.001), with no differences in elevation between conditions (all ps > 0.15). At T1 and T5, and the IQOSTM (T1 and T5, all ps > 0.42). Overall, the same patterns were found for the subscale “The smoking resulted in lower craving scores compared to vaping (all ps < 0.01) and compared to using desire and intention to smoke with an anticipation of pleasure from smoking”. The subscale “The relief from the IQOSTM (all ps < 0.01). No differences were observed at any moment between using the e-cigarette and the IQOSTM (T1 and T5, all ps > 0.42). Overall, the same patterns were found for the subscale “The desire and intention to smoke with an anticipation of pleasure from smoking”. The subscale “The relief from

Int. J. Environ. Res. Public Health 2018, 15, 2902 9 of 20 Int. J. Environ. Res. Public Health 2018, 15, x FOR PEER REVIEW 9 of 20 nicotinenicotine withdrawal withdrawal or or negative negative affect affect with with an an urgent urgent and and overwhelming overwhelming desire desire to to smoke smoke”,”, did did not not show show an an interaction-effect,interaction-effect, between between conditions conditions and and moments, moments, FF << 1. 1.

Cigarette E-cigarette IQOS 100

90

80

70

60

50

40 VAS cigarette craving 30

20

10

0 T0 T1 T2 T3 T4 T5

LABORATORY SESSION

Figure 3. Visual Analogue Scale (VAS) cigarette craving. Cigarette: MT0 (SE between brackets) = 65.00

(4.13), MT1 = 21.17 (3.71), MT2 = 23.23 (4.01), MT3 = 30.87 (4.17), MT4 = 36.67 (4.06), MT5 = 45.33 (4.05); FigureE-cigarette 3. Visual: MT0 Analogue= 65.07 (4.07), Scale (VAS)MT1 = cigarette 38.70 (3.88), craving.MT2 =Cigarette 43.20 (3.57),: MT0M (SET3 between= 47.73 (3.21), brackets)MT4 == 65.00 51.40 TM (4.13),(3.29), MMT1T5 = =21.17 60.43 (3.71), (3.05); MIQOST2 = 23.23: M (4.01),T0 = 68.17 MT3 = (4.08), 30.87M (4.17),T1 = 40.47 MT4 (4.94),= 36.67M (4.06),T2 = 43.70 MT5 (4.77),= 45.33M (4.05);T3 = 46.27 E- cigarette(4.71), M: T4MT0= = 51.53 65.07 (4.40), (4.07),M MT5T1= =58.20 38.70(3.89). (3.88), MT2 = 43.20 (3.57), MT3 = 47.73 (3.21), MT4 = 51.40 (3.29), MT5 = 60.43 (3.05); IQOSTM: MT0 = 68.17 (4.08), MT1 = 40.47 (4.94), MT2 = 43.70 (4.77), MT3 = 46.27 (4.71), 3.3.2. Withdrawal Symptoms (MNWS-R) MT4 = 51.53 (4.40), MT5 = 58.20 (3.89). At the start of each session (T0), participants reported relatively little withdrawal symptoms 3.3.2.after Withdrawal 12 h of smoking Symptoms abstinence (MNWS-R) (MCIG = 13.93, SECIG = 1.32; ME-CIG = 15.20, SEE-CIG = 1.58; andAtM theIQOS start= 13.63,of eachSE sessionIQOS = (T0), 1.42), participants with no differencesreported relatively between little conditions withdrawal (all symptomsps > 0.36; see AppendixA, Table A4). However, smoking and using the IQOS TM resulted in significant reductions after 12 h of smoking abstinence (MCIG = 13.93, SECIG = 1.32; ME-CIG = 15.20, SEE-CIG = 1.58; and MIQOS = in withdrawal symptoms (T0 to T1: both ps < 0.001), followed by a stagnation until the end of the 13.63, SEIQOS = 1.42), with no differences between conditions (all ps > 0.36; see Appendix A, Table A4). However,session (T1 smoking to T5: and both usingps > 0.10).the IQOS VapingTM resulted did not in resultsignificant in an reductions immediate in reduction withdrawal of withdrawalsymptoms (T0symptoms, to T1: bothF(1, ps 29) < 0.001), = 2.84 ,followedp = 0.10, by but a stagnation from T1 to until the endthe end of the of studythe session a decrease (T1 to wasT5: both observed, ps > 0.10).F(1, 29)Vaping = 15.31 did, p not< 0.001.result in At an T5, imme no differencesdiate reduction in withdrawal of withdrawal symptoms symptoms, were F(1, present 29) = 2.84, between p = TM TM 0.10,smoking but from and T1 using to the the end IQOS of the, nor study between a decrease vaping was and observed, using the F IQOS(1, 29) = ,15.31, both pps < > 0.001. 0.11, butAt T5, vaping no differencesresulted in in slightly withdrawal higher withdrawalsymptoms were symptoms present compared between to smoking smoking, andF(1, using 29) = 4.55,the IQOSp < 0.05.TM, nor between vaping and using the IQOSTM, both ps > 0.11, but vaping resulted in slightly higher 3.3.3. Product Evaluation and Preferences withdrawal symptoms compared to smoking, F(1, 29) = 4.55, p < 0.05. At T1 of each session, the mCEQ was administrated to evaluate the reinforcing effects of using 3.3.3.the differentProduct Evaluation products. Forand eachPreferences subscale, a main effect was found of the product that was used (all ps < 0.05; see Figure4 and AppendixA, Table A5). First, “ Satisfaction” was rated the highest after At T1 of each session, the mCEQ was administrated to evaluate the reinforcing effects of using smoking, followed by using the IQOSTM and vaping. Smoking appeared to be more satisfying than the different products. For each subscale, a main effect was found of the product that was used (all both vaping and using the IQOSTM, and using the IQOSTM was also more satisfying than vaping. ps < 0.05; see Figure 4 and Appendix A, Table A5). First, “Satisfaction” was rated the highest after Second, “Psychological reward” was for all products rated between very little and moderately, with again smoking, followed by using the IQOSTM and vaping. Smoking appeared to be more satisfying than the cigarette being superior, followed by the IQOSTM and then the e-cigarette. Third, the “Aversion” both vaping and using the IQOSTM, and using the IQOSTM was also more satisfying than vaping. subscale was rated relatively low, with smoking resulting in the highest scores, similar to the scores Second, “Psychological reward” was for all products rated between very little and moderately, with after vaping. After using the IQOSTM,“Aversion” scores were significantly lower, compared to smoking again the cigarette being superior, followed by the IQOSTM and then the e-cigarette. Third, the “Aversion” subscale was rated relatively low, with smoking resulting in the highest scores, similar to

Int. J. Environ. Res. Public Health 2018, 15, x FOR PEER REVIEW 10 of 20 Int. J. Environ. Res. Public Health 2018, 15, x FOR PEER REVIEW 10 of 20 Int.the J.scores Environ. after Res. vaping. Public Health After2018 using, 15, 2902 the IQOSTM, “Aversion” scores were significantly lower, compared 10 of 20 the scores after vaping. After using the IQOSTM, “Aversion” scores were significantly lower, compared to smoking and to vaping. Fourth, the “Enjoyment of respiratory tract sensations” was experienced a lot to smoking and to vaping. Fourth, the “Enjoyment of respiratory tract sensations” was experienced a lot after smoking, little to moderately after using the IQOSTM, and very little to not at all after vaping. andafter to smoking, vaping. Fourth,little to the moderately “Enjoyment after of respiratory using the tract IQOS sensationsTM, and” very was experiencedlittle to not at a lot all after after smoking, vaping. Lastly, the results of the “Craving reduction” subscale were in line with the previously reported VASs littleLastly, to the moderately results of after the using“Craving the reduction IQOSTM,” andsubscale very littlewere toin notline at with all after the previously vaping. Lastly, reported the results VASs and QSU-Brief results. More specifically, smoking resulted in the highest craving reduction, followed ofand the QSU-Brief “Craving results. reduction More” subscale specifically, were smoking in line with resulted the previously in the highest reported craving VASs reduction, and QSU-Brief followed by using the IQOSTM, and vaping. Using the IQOSTM and vaping resulted in similar scores, with results.by using More the specifically,IQOSTM, and smoking vaping. resultedUsing the in theIQOS highestTM and craving vaping reduction, resulted in followed similar byscores, using with the smoking showing significantly higher craving reduction scores, compared to vaping and using the IQOSsmokingTM, andshowing vaping. significantly Using the IQOShigherTM cravingand vaping reduction resulted scores, in similar compared scores, to with vaping smoking and using showing the IQOSTM. TM significantlyIQOSTM. higher craving reduction scores, compared to vaping and using the IQOS .

Figure 4. Modified Cigarette Evaluation Questionnaire (mCEQ) subscales. (a) “Satisfaction”; (b) FigureFigure 4. ModifiedModified Cigarette Cigarette Evaluation Evaluation Qu Questionnaireestionnaire (mCEQ) (mCEQ) subscales. subscales. (a) (“aSatisfaction)“Satisfaction”; (b”;) “Psychological reward“; (c) “Aversion“; (d) “Enjoyment of respiratory tract sensations“; (e) “Craving (“bPsychological)“Psychological reward reward“; (“;c) (c“)“AversionAversion“; “;(d ()d “)“EnjoymentEnjoyment of of respiratory respiratory tract tract sensations “;“; ( e))“ “CravingCraving reduction”; for (a–e): * p < 0.05, ** p < 0.01, *** p < 0.001. reductionreduction”;”; forfor (a–e):(a–e): ** pp << 0.05, ** p < 0.01, *** p < 0.001. 0.001.

On the individual VASs forfor thethe e-cigarettee-cigarette andand IQOSIQOSTMTM,, at at the the end end of of the laboratory sessions, sessions, On the individual VASs for the e-cigarette and IQOSTM, at the end of the laboratory sessions, participants reported only a significantly higher willingness to use theTM IQOSTM for another five participantsparticipants reportedreported only only a significantlya significantly higher higher willingness willingness to use to the use IQOS the IQOSfor anotherTM for another five minutes five minutes compared to the e-cigarette, see Figure 5a (see also Appendix A, Table A6). For all other comparedminutes compared to the e-cigarette, to the e-cigarette, see Figure see5a Figure (see also 5a Appendix(see also AAppendix, Table A6 A,). Table For all A6). other For items all other no items no differences were found, although in absolute terms theTM IQOSTM obtained higher scores. This differencesitems no differences were found, were although found, al inthough absolute in termsabsolute the terms IQOS the obtainedIQOSTM obtained higher scores. higher This scores. pattern This pattern was also observed in the VASs, where participants indicated their preferred choice on the waspattern also was observed also observed in the VASs, in the where VASs, participants where part indicatedicipants theirindicated preferred their choicepreferred onthe choice four on items, the four items, see Figure 5b. The mean scores, indicating a preference for theTM IQOSTM, wereSD 67.27 (SD = seefour Figure items,5 b.see TheFigure mean 5b. scores,The mean indicating scores, indicati a preferenceng a preference for the IQOS for the ,IQOS wereTM 67.27, were ( 67.27= 39.23), (SD = 39.23), 65.63 (SD = 39.90), 64.13 (SD = 41.28), and 69.37 (SD = 39.38), respectively. However, variation 65.6339.23), (SD 65.63= 39.90),(SD = 39.90), 64.13 (64.13SD = ( 41.28),SD = 41.28), and 69.37and 69.37 (SD =(SD 39.38), = 39.38), respectively. respectively. However, However, variation variation in in product preferences was large among the participants. productin product preferences preferences was was large large among among the the participants. participants.

Figure 5. Additional VASs onon DayDay 3.3. ((aa)) PreferencesPreferences forfor e-cigarettee-cigarette andand IQOSIQOSTMTM,, separately, separately, with 0 Figure 5. Additional VASs on Day 3. (a) Preferences for e-cigarette and IQOSTM, separately, with 0 being ““NotNot atat all all”” and and 100 100 “Very “Very much much so”; so (”;b) ( Productb) Product preference preference with with 0 being 0 being “E-cigarette “E-cigarette” and” 100 and being 100 being “Not at all” and 100 “Very much so”; (b) Product preference with 0 being “E-cigarette” and 100 ”beingIQOS ””;IQOS for both”; for (a both and (a b) and * p < b) 0.05. * p < 0.05. being ”IQOS”; for both (a and b) * p < 0.05. TM Participants reported aspects theythey missedmissed whenwhen usingusing thethe e-cigarettee-cigarette andand thethe IQOSIQOSTM compared Participants reported aspects they missed when using the e-cigarette and the IQOSTM compared to tobacco cigarettes. Mentioned themes, including frequency of reporting by participants, were the following:to tobacco cigarettes. (a) the taste, Mentioned aroma, flavor,themes, or including smell (e-cigarette: frequency of 63% reporting of participants; by participants, IQOSTM were: 63%); the

Int. J. Environ. Res. Public Health 2018, 15, 2902 11 of 20

(b) the psychophysiological effects of having used the product, such as experiencing relaxing effects (e-cigarette: 43%; IQOSTM: 27%); (c) the feeling/sensations of inhalation in the throat and lungs (e-cigarette: 27%; IQOSTM: 27%); (d) the nicotine and throat hit (e-cigarette: 23%; IQOSTM: 20%); and (e) the handling/gesture of smoking (e-cigarette: 17%; IQOSTM: 23%). Six participants (20%) reported no missing aspects for the e-cigarette and nobody (0%) did so for the IQOSTM. Secondly, also the strengths of both products were questioned. Themes reported included (a) better for health or less harmful (e-cigarette: 47%; IQOSTM: 53%); (b) the taste, aroma, flavor or smell (e-cigarette: 27%; IQOSTM: 17%); (c) the lack of any odor/smell after use (e-cigarette: 13%; IQOSTM: 20%); and (d) the psychophysiological effect (e-cigarette: 0%; IQOSTM: 23%). Seven participants (23%) reported no strengths of the e-cigarette and three (10%) reported no strengths of the IQOSTM.

4. Discussion The current study, using a randomized, cross-over, counterbalanced, within-subjects design, investigated the effects of using the IQOSTM HnB product compared to smoking and vaping, in overnight-abstinent regular smokers, who were novice users of e-cigarettes and HnB products. First, eCO levels decreased significantly from Intake to T0, with at T0 average eCO levels (about 3 ppm) approaching that of nonsmokers. These results seemed to confirm compliance to the abstinence rule. However, some participants spontaneously mentioned at Intake that they also did not smoke before that session, potentially explaining the relatively low eCO levels at Intake for these regular smokers. Perhaps the recruitment information was confusing concerning the abstinence rules. In addition, as observed in several other studies, our data reconfirmed that vaping does not result in any change of eCO levels [13]. As expected, after five minutes of smoking eCO levels increased significantly until T2, after which the levels slowly started to decrease again. Surprisingly, a similar pattern was observed after using the IQOSTM, but the increase in the eCO levels was only 11% (0.3 ppm) of the baseline values (T0 to T1), with a maximum increase of 27% (T0 to T2; 0.8 ppm), whereas, these percentages after smoking reached 135% (4.2 ppm) and 153% (4.7 ppm) of the baseline values, respectively. At first sight, these results seemed to conflict with those obtained in the study of Caponnetto and colleagues, where no significant increase was found in the eCO levels after using the two HnB products [60]. However, looking at the absolute eCO levels after the IQOSTM use in the Caponnetto study, a small increase occurred up to 15 min, after using the IQOSTM (maximum level during session: 4.9 ppm vs. 3.5 ppm in our study), after which the eCO levels started to decline again [60]. A plausible explanation for this nominal increase not reaching significance, is a lack of statistical power in the study of Caponnetto and colleagues—they only included 12 participants, whereas we included 30. This minor and clinically non-significant increase in the eCO levels after using the IQOSTM, is in line with the previously documented presence of CO in the aerosol of the IQOSTM, albeit at a low level of 0.53 mg/stick (which is only 1.6% of the CO in the aerosol of the 3R4F reference cigarette (32.8 mg/stick)) [38,42,60]. Namely, although no combustion takes place due to the limited heating up to 350◦C when an IQOSTM is used, CO may also be generated by (low-temperature) pyrolysis [72–74]. Second, after 12 h of smoking abstinence, participants reported moderate cigarette craving at the start of each session. Five minutes of use of each product resulted in significant decreases in cigarette craving, but smoking resulted in a craving reduction of 44%, whereas vaping and using the IQOSTM only resulted in a reduction of 26% and 28%, respectively. Throughout the remaining time of the session, cigarette craving slightly increased again. These results were confirmed by the QSU-Brief questionnaire. Comparison with the studies from the PMI is difficult due to the very nature of our short-term, cross-over design, whereas PMI mainly used confinement studies to investigate the effects of the IQOSTM over the course of several days of use [44–49]. In these multi-day studies, it was observed that using an IQOSTM can be equally effective in controlling cigarette craving as smoking cigarettes [44–49]. Even though we did not find such pronounced effects, we likewise observed that cigarette-craving was substantially reduced after five minutes of IQOSTM use, and about as much as that after five minutes of vaping, but clearly less than that after smoking. Int. J. Environ. Res. Public Health 2018, 15, 2902 12 of 20

Third, although moderate levels of cigarette craving were reported by participants in each session, little withdrawal symptoms were reported. Nevertheless, after smoking and using the IQOSTM alike, withdrawal symptoms decreased immediately, while for vaping this occurred with some delay. In one of the confinement studies, Lüdicke and colleagues also found that using the IQOSTM resulted in similar reductions in withdrawal symptoms, as that after smoking [48]. A possible explanation for the delay in a reduction of the withdrawal symptoms for vaping, is that the blood nicotine delivery of an e-cigarette may be slower than that of a combustible cigarette, and possibly also slower than that of an IQOSTM [44,75]. In addition, participants were novice users and only had five minutes time to familiarize with the e-cigarette, which can also have resulted in less nicotine uptake and, in turn, a slower decrease of withdrawal symptoms [75]. It has been shown that longer puffs (4 s) from an e-cigarette are needed to deliver nicotine to the aerosol at levels approaching those of cigarettes, a behavior topography which probably is lacking in novice users [53]. Interestingly, in the same study, nicotine delivery to the aerosol of the IQOSTM was shown not to be affected by puff duration, such that cigarette-like puffing behavior (e.g., short 2 s puffs) would not adversely affect nicotine delivery [53]. In other words, a plausible hypothesis may be that using an IQOSTM, but not an e-cigarette, in a smoking-like fashion (in terms of puff-topography) would result in nicotine pharmacokinetics closely mimicking those of smoking, such that a learning curve plays less of a role than for vaping. Fourth and lastly, each product was evaluated by participants after a first-time, five-minutes-use (T1). All subscales of the mCEQ (“Smoking satisfaction”, “Psychological reward”, “Aversion”, “Enjoyment of respiratory tract sensations”, and “Craving reduction”) were rated lower for the IQOSTM than for the tobacco cigarette. At the same time, IQOSTM was evaluated better, compared to the e-cigarette concerning “Smoking satisfaction”, “Psychological reward”, and “Enjoyment of respiratory tract sensations”. These results are in line with results from PMI; more specifically, across a period of five days of confinement or across a 30-day period, all subscales of the mCEQ were also scored lower for the IQOSTM compared to the cigarette (except for the Aversion-scale scores which were similar) [46–48]. In addition to the mCEQ, we asked participants to report their preferences regarding the IQOSTM and e-cigarette. In general, the IQOSTM was rated slightly higher than the e-cigarette on all preference scales, but only for “wanting to use the product another five minutes” there was a reliable difference. All results obtained should be seen in the light of the following limitations. First, the results and interpretations of these results are based on a small convenience sample. It is possible that this sample is not representative for the average regular smoker. Almost all participants were students, relatively young, and not highly cigarette dependent. Second, participants only received a brief explanation on how to use the two products, which were new for them, and they got no more than five minutes to use each product as much or as little as they wanted. This short-term use can as well have had an impact on the results. In the studies of PMI, participants were five days in confinement, and needed to switch completely to the IQOSTM. In that case, participants got the opportunity to become more familiar with the product and to gain more knowledge on how to use the IQOSTM in the most effective way. Finally, and probably most importantly, for both the HnB product and the e-cigarette, we used just one specific type. Whereas the offer of the different HnB products is rather limited, a plethora of types of e-cigarettes and of flavors of e-liquids, with various nicotine concentrations exists, which may well differ with respect to the effect on the behavioral and experiential variables studied here. Therefore, one should be very cautious extrapolating these results to other types of HnB products and most of all, to other types of e-cigarettes.

5. Conclusions To conclude, within the framework of THR, in which smokers ideally should be able to freely choose from a variety of less harmful alternatives for smoking, HnB products seem to have the potential of a promising new offering. Our study namely showed that short-term use of a specific HnB product, IQOSTM, can be effective to momentarily reduce acute cigarette craving and withdrawal symptoms, Int. J. Environ. Res. Public Health 2018, 15, 2902 13 of 20 while having a minimal impact on the eCO levels, and being slightly more liked by novice users than an e-cigarette. While these short-term effects are promising, they do of course not guarantee that craving/withdrawal reduction will also be sustained over longer time spans or in case of repeated use, nor do they provide assurance that these effects are sufficient to lead to smoking reduction or cessation in smokers willing to quit or cut down on cigarettes. Therefore, it will be important to further independently investigate the effects of HnB products in the long-term, not only with respect to health-effects, but also with respect to their potential as a (partial, or preferably, complete) substitute for smoking cigarettes.

Author Contributions: K.A. developed the study design together with F.B. and D.V.G., and all authors contributed to the establishment of the analysis plan. K.A. was responsible for the data collection, conducted the analyses, and all authors contributed to the interpretation of the results. K.A. drafted the main manuscript and all authors revised, read, and approved the final manuscript. Funding: This research received no external funding. Acknowledgments: The authors would like to thank Juan Felipe Gutiérrez Pineda for his extensive assistance in collecting the data. Conflicts of Interest: The authors declare no conflict of interest but are advocates for Tobacco Harm Reduction (THR).

Appendix A.

Table A1. Smoking history and current smoking behavior.

Variable n M (SD) or % Smoking history Age start smoking 30 16.17 (1.84) Age start smoking regularly 30 17.90 (1.77) Number of years smoking regularly 30 4.47 (1.98) Tried to quit smoking in the past (no/yes) 20/10 66.67/33.33 Number of past quit smoking attempts 10 2.00 (0.94) Quit-smoking aids used * 10 E-cigarette 1 10.00 NRT 0 0.00 Smoking cessation medication 0 0.00 Counseling 0 0.00 None-willpower 9 90.00 Other (e.g., book) 2 20.00 Longest period quit smoking in months 10 5.20 (9.02) Quit-smoking aids used longest quit smoking period 10 E-cigarette 0 0.00 NRT 0 0.00 Smoking cessation medication 0 0.00 Counseling 0 0.00 None-willpower 10 100.00 Other (e.g., book) 0 0.00 Current smoking behavior CPD 30 12.73 (3.62) eCO 30 7.37 (3.39) Situations when smoking * 30 Drinking alcohol 29 96.67 With others 28 93.33 After a meal 26 86.67 Alone 25 83.33 Going somewhere (car, walking, . . . ) 22 73.33 At a café 19 63.33 At home 18 60.00 Drinking coffee 14 46.67 At work/school 13 43.33 Int. J. Environ. Res. Public Health 2018, 15, 2902 14 of 20

Table A1. Cont.

Variable n M (SD) or % Immediately after getting up 12 40.00 During stress 10 33.33 Other (e.g., during breaks, when waiting) 10 33.33 Watching TV 5 16.67 Reasons why smoking * 30 For relaxation 26 86.67 Feeling like having a cigarette 25 83.33 For atmosphere and sociability 24 80.00 Out of habit 23 76.67 For pleasure and enjoyment of it 21 70.00 For stress reduction 20 66.67 Out of boredom 12 40.00 Other (e.g., pastime, gesture/handling) 9 30.00 For nicotine 8 26.67 Most important cigarette 30 First one of the day 8 26.67 After a meal 6 20.00 Last one of the day 6 20.00 After class/work 4 13.33 Other (e.g., with coffee, with friends) 6 20.00 Cigarette brand 25 Lucky strike 7 28.00 Marlboro 7 28.00 Camel or Lucky strike 3 12.00 Camel 3 12.00 Other (e.g., Tigra, Wintson) 5 20.00 Cigarette type 29 Filter cigarette 23 79.31 Self-rolled cigarette 5 17.24 Filter and self-rolled cigarettes 1 3.45 Currently trying to reduce smoking (no/yes) 26/4 86.67/13.33 Motivation to quit smoking 30 No intention of quitting at all 26 86.67 No intention of quitting at all, but open for less 1 3.33 harmful alternatives Considering quitting smoking, but no concrete plans 2 6.67 Concrete plans to quit smoking in next 3 months 1 3.33 Experienced negative health effects of smoking 30 2.23 (0.48) FTCD-score 30 3.50 (1.96) Suffering from any psychological/psychiatric 30 condition No 29 96.67 Yes 0 0.00 Prefer not to say 1 3.33 Note: * multiple responses were possible.

Table A2. ANOVA summary table for eCO level.

Source df MS F p Intercept 1 13897.91 215.56 0.0000 *** Error 29 64.47 Product 2 628.11 71.00 0.0000 *** Error 58 8.85 Moment 6 162.97 37.40 0.0000 *** Error 174 4.36 Product × Moment 12 38.95 70.39 0.0000 *** Error 348 0.55 Note: *** significant with α level 0.001; Product includes IQOSTM, e-cigarette, and tobacco cigarette; Moment includes intake and laboratory session T0–T5. Int. J. Environ. Res. Public Health 2018, 15, 2902 15 of 20

Table A3. ANOVA summary table for cigarette craving.

VAS Cigarette Craving Source df MS F p Intercept 1 1167987.03 243.41 0.000 *** Error 29 4798.49 Product 2 12092.99 12.49 0.000 *** Error 58 968.26 Moment a 5 13317.59 54.20 0.000 *** Error 145 245.73 Product × Moment 10 462.33 5.75 0.000 *** Error 290 80.45 QSU-Brief–Total score Source df MS F p Intercept 1 2857.73 392.44 0.0000 *** Error 29 7.28 Product 2 9.23 10.29 0.0001*** Error 58 0.90 Moment b 2 88.68 82.98 0.0000 *** Error 58 1.07 Product × Moment 4 1.38 3.61 0.0082 ** Error 116 0.38 QSU-Brief–Subscale “The desire and intention to smoke with an anticipation of pleasure from smoking” Source df MS F p Intercept 1 4612.80 518.69 0.0000 *** Error 29 8.89 Product 2 16.11 11.45 0.0001 *** Error 58 1.41 Moment b 2 154.21 107.43 0.0000 *** Error 58 1.44 Product × Moment 4 3.48 5.79 0.0002 *** Error 116 0.60 QSU-Brief–Subscale “The relief from nicotine withdrawal or negative affect with an urgent and overwhelming desire to smoke” Source df MS F p Intercept 1 1266.06 179.51 0.0000 *** Error 29 7.05 Product 2 2.87 4.30 0.0182 * Error 58 0.67 Moment b 2 29.98 36.32 0.0000 *** Error 58 0.83 Product × Moment 4 0.16 0.60 0.6635 Error 116 0.27 Note: * significant with α level 0.05; ** significant with α level 0.01; *** significant with α level 0.001. Product includes IQOSTM, e-cigarette, and tobacco cigarette; Moment a includes laboratory session T0–T5; Moment b includes laboratory session T0, T1, and T5.

Table A4. ANOVA summary table for the Revised Minnesota Nicotine Withdrawal Scale (MNWS-R) total scores.

Source df MS F p Intercept 1 34138.13 129.52 0.0000 *** Error 29 263.58 Product 2 238.14 5.80 0.0050 ** Error 58 41.03 Moment 2 622.34 32.60 0.0000 *** Error 58 19.09 Product × Moment 4 42.52 3.78 0.0063 ** Error 116 11.24 Note: ** significant with α level 0.01; *** significant with α level 0.001; Product includes IQOSTM, e-cigarette, and tobacco cigarette; Moment includes laboratory session T0, T1, and T5. Int. J. Environ. Res. Public Health 2018, 15, 2902 16 of 20

Table A5. ANOVA summary table for mCEQ.

Subscale “Satisfaction” Source df MS F p Intercept 1 1491.11 765.65 0.0000 *** Error 29 1.95 Product 2 52.06 37.87 0.0000 *** Error 58 1.37 Subscale “Psychological reward” Source df MS F p Intercept 1 978.78 405.23 0.0000 *** Error 29 2.42 Product 2 9.21 14.01 0.0000 *** Error 58 0.66 Subscale “Aversion” Source df MS F p Intercept 1 422.50 165.20 0.0000 *** Error 29 2.56 Product 2 4.08 4.62 0.0138 * Error 58 0.88 Subscale “Enjoyment of respiratory tract sensations” Source df MS F p Intercept 1 1047.21 513.67 0.0000 *** Error 29 2.04 Product 2 80.58 36.65 0.0000 *** Error 58 2.20 Subscale “Craving reduction” Source df MS F p Intercept 1 1876.90 673.92 0.0000 *** Error 29 2.79 Product 2 25.03 11.78 0.0001 *** Error 58 2.13 Note: * significant with α level 0.05; *** significant with α level 0.001; Product includes IQOSTM, e-cigarette and tobacco cigarette.

Table A6. T-test results for additional VASs day 3.

E-CIG HnB Product Variable–VAS Statistic p-Value M (SD) M (SD) Willing to use the product for another five minutes 30.70 (27.87) 49.47 (29.34) t(29) = −2.36 0.0251 * Willing to keep trying or start using the product 41.93 (30.82) 53.90 (29.52) t(29) = −1.42 0.1673 Desire/intention to go and buy the product 22.43 (26.90) 33.83 (27.38) t(29) = −1.79 0.0842 Willing to consider using the product to (try to) quit smoking 35.83 (29.64) 48.60 (34.63) t(29) = −1.56 0.1286 Note: * significant with α level 0.05.

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